Diabetes mellitus is the most common metabolic disease worldwide. Every day, 1700 new cases of diabetes are diagnosed in the United States, and at least one-third of the 16 million Americans with diabetes are unaware of it. Diabetes is the leading cause of blindness, renal failure, and lower limb amputations in adults and is a major risk factor for cardiovascular disease and stroke.
Normal glucose homeostasis requires the finely tuned orchestration of insulin secretion by pancreatic beta cells in response to subtle changes in blood glucose levels, delicately balanced with secretion of counter-regulatory hormones such as glucagon. Type 1 diabetes results from autoimmune destruction of pancreatic beta cells causing insulin deficiency. Type 2 or noninsulin-dependent diabetes mellitus (NIDDM) accounts for  greater than 90% of cases and is characterized by a triad of (1) resistance to insulin action on glucose uptake in peripheral tissues, especially skeletal muscle and adipocytes, (2) impaired insulin action to inhibit hepatic glucose production, and (3) dysregulated insulin secretion (DeFronzo, (1997) Diabetes Rev. 5:177-269). In most cases, type 2 diabetes is a polygenic disease with complex inheritance patterns (reviewed in Kahn et al., (1996) Annu. Rev. Med. 47:509-531).
Environmental factors, especially diet, physical activity, and age, interact with genetic predisposition to affect disease prevalence. Susceptibility to both insulin resistance and insulin secretory defects appears to be genetically determined (Kahn, et al). Defects in insulin action precede the overt disease and are seen in nondiabetic relatives of diabetic subjects. In spite of intense investigation, the genes responsible for the common forms of Type 2 diabetes remain unknown.
One of the fundamental actions of insulin is to stimulate uptake of glucose from the blood into tissues, especially muscle and fat. This occurs via facilitated diffusion which is mediated by specific glucose transporter proteins that insert into the plasma membrane of cells. GLUT4 is the most important insulin-sensitive glucose transporter in these tissues. Insulin binds to its receptor in the plasma membrane, generating a series of signals that result in the translocation or movement of GLUT4 transporter vesicles to the plasma membrane, where a first docking step, followed by fusion with the plasma membrane takes place; after an activation or exposure step takes place, glucose enters the cell. Studies in both animals and humans indicate that alterations in GLUT4 expression, trafficking, and/or activity occur in adipose cells and muscle in diabetes and other insulin-resistant states (Abel et al., Diabetes Mellitus: A Fundamental and Clinical Text (1996) pp.530-543.)
New and innovative treatments for diabetes are clearly a priority for researchers in this field. The present invention provides such innovative treatments, taking advantage of the knowledge concerning GLUT4 expression and activity, and expression and activity of related hexose transporters (e.g., GLUT1).
The present invention provides a method of treating diabetes and related diseases, such as obesity, by administering to a subject an inhibitor of GDF-8. Suitable inhibitors of GDF-8 which can be employed in the methods of the invention include, but are not limited to, GDF-8 peptides (e.g., derived from the pro-domain), GDF-8 dominant-negative mutants, antibodies and antibody fragments which bind to GDF-8 (or the receptor for GDF-8) and inhibit GDF-8 binding to its receptor, GDF-8 receptor peptide antagonists, antisense nucleic acids directed against GDF-8 mRNA and anti-GDF-8 ribozymes.
In another aspect, the present invention provides a method of increasing GLUT4 expression in a cell (e.g., a muscle cell or a fat cell in a subject), or increasing glucose uptake by a cell, by administering a GDF-8 inhibitor. Such methods can be used, not only to treat diabetes and related diseases, but also to treat several systemic problems resulting from insufficient glucose metabolism, such as hyperglycemia.
The methods of the present invention also can be performed using as targets other TGF-xcex2 growth factors which are related in structure and activity to GDF-8, such as GDF-11. Accordingly, in another embodiment, the invention provides method of treating diabetes by administering to a subject an inhibitor of GDF-11, either alone or in combination with other GDF inhibitors (e.g., an inhibitor of GDF-8).